Project Summary The nucleus reuniens (RE) of the thalamus lies ventrally on the midline of the thalamus and is the largest of the midline nuclei of the thalamus. The nucleus reuniens is intimately connected with structures of the limbic system ? or a system of the brain that deals with affect, memory, and cognition. Specifically, RE receives a vast array of input from limbic-related structures, and predominantly directs its output to limbic cortical structures, primarily to the hippocampal formation (HF) and to the prefrontal cortex (PFC). Both structures serve a prominent role in various aspects of memory. With respect to the functional role of RE, it has recently been shown that lesions (or inactivation) RE produce attentional deficits, presumably involving the disruption of RE connections with the PFC, and severe deficits in working memory involving the loss of RE actions on the hippocampus. As RE is strategically positioned to influence executive functions of the prefrontal cortex and mnemonic functions of the hippocampus, it has been directly implicated in several neurological disorders in which these functions are disrupted, including alterations of consciousness, Alzheimer?s disease, epilepsy, and schizophrenia. With the present proposal, we intend to continue our investigation of nucleus reuniens by focusing on its role in mnemonic processing and executive functions, such as attention and behavioral flexibility, which rely on the hippocampus and the orbitomedial prefrontal cortex. This will be done by the following. 1. By examining the activity of single cells of RE during natural sleep- waking states with the expectation that RE cells would show differential changes across stages of sleep and waking that would provide important insight into the state specific effects of RE on the hippocampus and the prefrontal cortex, as revealed by the relationship of RE cellular activity to local field potentials of the HF and prefrontal cortex. 2. By examining the effects of inactivating RE, per se, or RE fibers targeting the HF or the orbitomedial PFC on an odor/texture attentional set shifting task (AST) which measures executive functions such as attention and behavioral flexibility with the expectation that disruption of RE will impair executive functions, particularly so with the suppression of RE fibers projecting to the ventral HF and the orbital cortex. 3. By examining the effects of inactivating nucleus reuniens or RE fibers to targets on a delayed alternation T-maze task that measures spatial working memory (SWM) with the expectation that disruption of RE would significantly alter performance on this task, particularly so with the suppression of RE fibers projecting to the dorsal HF and to the medial PFC. 4. By examining the activity of RE cells in the T-maze task with the expectation that RE neurons would discharge in manner indicative of a transfer of information between the HF and the medial PFC (via RE), leading to the successful performance on this task. We believe that this series of experiments will serve to demonstrate that nucleus reuniens plays a very critical role in working memory and executive functions in conjunction with direct effects on the hippocampus and PFC. In addition, these studies should provide important information on the modulatory role of RE on attentional and cognitive processes which are altered in several neurological disorders including failures of consciousness, Alzheimer?s disease, schizophrenia, and epilepsy.